: Peroxisome proliferator chemicals (PPCs) activate peroxisome proliferator activated receptor (PPARalpha), and thereby induce a variety of toxicological responses, which are particularly striking in rodents. These include hepatic peroxisome proliferation, liver hypertrophy, an increase in replicative DNA synthesis, suppression of apoptosis, and ultimately, hepatocarcinogenesis. The suppression of apoptosis by PPCs is thought to play a critical role in the imbalance between cell proliferation and cell death, which ultimately leads to hepatocarcinogenesis in rodents. The impact of these chemicals on human health is uncertain, prompting studies to elucidate the underlying mechanism for the hepatotoxic responses. Because PPC suppression of apoptosis is a control step in the hepatocarcinogenesis, the goal of this proposal is to investigate the mechanism of action for the PPC-induced inhibition of apoptosis through studies of the cross-talk between PPC-activated PPARalpha and intracellular signaling pathways that regulate apoptosis. One hypothesis to explain PPC-induced hepatocarcinogenesis is an increase in DNA damage through an elevation of H2O2. The transcription factors NFkB and Nrf2 are activated in response to reactive oxygen species, suggesting that these transcription factors may play a critical role in PPC-induced carcinogenesis. Therefore, Aim I will investigate the role of NFkB and Nrf2 signaling in the PPC-induced suppression of apoptosis. Other factors implicated in the control of apoptotic signaling are the STAT transcription factors. STATs regulate cellular functions of proliferation, differentiation, apoptosis, and can alternatively stimulate or inhibit apoptosis responses. Aim II will focus on the role of cytokine- and growth factor-activated STATs 1,3 and 5b in the suppression of apoptosis by PPC-activated PPARalpha. The proposed studies will provide valuable mechanistic information for the toxicological responses of liver to PPARalpha, and will thus aid in determining the extent to which humans are at risk for PPC-induced carcinogenesis.